This invention is in the area of methods for the treatment of hepatitis B virus (also referred to as xe2x80x9cHBVxe2x80x9d) that includes administering to a host in need thereof, either alone or in combination, an effective amount of one or more of the active compounds disclosed herein, or a pharmaceutically acceptable prodrug or salt of one of these compounds.
HBV is second only to tobacco as a cause of human cancer. The mechanism by which HBV induces cancer is unknown, although it is postulated that it may directly trigger tumor development, or indirectly trigger tumor development through chronic inflammation, cirrhosis, and cell regeneration associated with the infection.
Hepatitis B virus has reached epidemic levels worldwide. After a two to six month incubation period in which the host is unaware of the infection, HBV infection can lead to acute hepatitis and liver damage, that causes abdominal pain, jaundice, and elevated blood levels of certain enzymes. HBV can cause fulminant hepatitis, a rapidly progressive, often fatal form of the disease in which massive sections of the liver are destroyed.
Patients typically recover from acute hepatitis. In some patients, however, high levels of viral antigen persist in the blood for an extended, or indefinite, period, causing a chronic infection. Chronic infections can lead to chronic persistent hepatitis. Patients infected with chronic persistent HBV are most common in developing countries. By mid-1991, there were approximately 225 million chronic carriers of HBV in Asia alone, and worldwide, almost 300 million carriers. Chronic persistent hepatitis can cause fatigue, cirrhosis of the liver, and hepatocellular carcinoma, a primary liver cancer.
In western industrialized countries, high risk groups for HBV infection include those in contact with HBV carriers or their blood samples. The epidemiology of HBV is very similar to that of acquired immune deficiency syndrome (AIDS), which accounts for why HBV infection is common among patients with AIDS or AIDS related complex. However, HBV is more contagious than HIV.
However, more recently, vaccines have also been produced through genetic engineering and are currently used widely. Unfortunately, vaccines cannot help those already infected with HBV. Daily treatments with xcex1-interferon, a genetically engineered protein, has also shown promise, but this therapy is only successful in about one third of treated patients. Further, interferon cannot be given orally.
A number of synthetic nucleosides have been identified which exhibit activity against HBV. The (xe2x88x92)-enantiomer of BCH-189, known as 3TC, claimed in U.S. Pat. No. 5,539,116 to Liotta, et al., has been approved by the U.S. Food and Drug Administration for the treatment of hepatitis B. See also EPA 0 494 119 A1 filed by BioChem Pharma, Inc.
Cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (xe2x80x9cFTCxe2x80x9d) exhibits activity against HBV. See WO 92/15308; Furman, et al., xe2x80x9cThe Anti-Hepatitis B Virus Activities, Cytotoxicities, and Anabolic Profiles of the (xe2x88x92) and (+) Enantiomers of cis-5-Fluoro-1-[2-(Hydroxymethyl)-1,3-oxathiolane-5-yl]-Cytosinexe2x80x9d Antimicrobial Agents and Chemotherapy, December 1992, page 2686-2692; and Cheng, et al., Journal of Biological Chemistry, Volume 267(20), 13938-13942 (1992).
von Janta-Lipinski et al. disclose the use of the L-enantiomers of 3xe2x80x2-fluoro-modified xcex2-2xe2x80x2-deoxyribonucleoside 5xe2x80x2-triphosphates for the inhibition of hepatitis B polymerases (J. Med. Chem., 1998, 41,2040-2046). Specifically, the 5xe2x80x2-triphosphates of 3xe2x80x2-deoxy-3xe2x80x2-fluoro-xcex2-L-thymidine (xcex2-L-FTTP), 2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-xcex2-L-cytidine (xcex2-L-FdCTP), and 2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluoro-xcex2-L-5-methylcytidine (xcex2-L-FMethCTP) were disclosed as effective inhibitors of HBV DNA polymerases.
WO 96/13512 to Genencor International, Inc. and Lipitek, Inc. discloses that certain L-ribofuranosyl nucleosides can be useful for the treatment of cancer and viruses. Specifically disclosed is the use of this class of compounds for the treatment of cancer and HIV.
U.S. Pat. Nos. 5,565,438, 5,567,688 and 5,587,362 (Chu, et al.) disclose the use of 2xe2x80x2-fluoro-5-methyl-xcex2-L-arabinofuranolyluridine (L-FMAU) for the treatment of hepatitis B and Epstein Barr virus.
Yale University and University of Georgia Research Foundation, Inc. disclose the use of L-FddC (xcex2-L-5-fluoro-2xe2x80x2,3xe2x80x2-dideoxycytidine) for the treatment of hepatitis B virus in WO 92/18517.
The synthetic nucleosides xcex2-L-2xe2x80x2-deoxycytidine (xcex2-L-2xe2x80x2-dC), xcex2-L-2xe2x80x2-deoxythymidine (xcex2-L-dT) and xcex2-L-2xe2x80x2-deoxyadenosine (xcex2-L-2xe2x80x2-dA), are known in the art. Antonin Holy first disclosed xcex2-L-dC and xcex2-L-dT in 1972, xe2x80x9cNucleic Acid Components and Their Analogs. CLIII. Preparation of 2xe2x80x2-deoxy-L-Ribonucleosides of the Pyrimidine Series,xe2x80x9d Collect. Czech. Chem. Commun. (1972), 37(12), 4072-87. Morris S. Zedeck et al. first disclosed xcex2-L-dA for the inhibition of the synthesis of induced enzymes in Pseudomonas testosteroni, Mol. Phys. (1967), 3(4),386-95.
Certain 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleoside are known to have antineoplastic and selected antiviral activities. Verri et al. disclose the use of 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleosides as antineoplastic agents and as anti-herpetic agents (Mol. Pharmacol. (1997), 51(1), 132-138 and Biochem. J. (1997), 328(1), 317-20). Saneyoshi et al. demonstrate the use of 2xe2x80x2-deoxy-L-ribonucleosides as reverse transcriptase (I) inhibitors for the control of retroviruses and for the treatment of AIDS, Jpn. Kokai Tokkyo Koho JP06293645 (1994).
Giovanni et al. tested 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleosides against partially pseudorabies virus (PRV), Biochem. J. (1993), 294(2), 381-5.
Chemotherapeutic uses of 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleosides were studied by Tyrsted et al. (Biochim. Biophys. Acta (1968), 155(2), 619-22) and Bloch, et al. (J. Med. Chem. (1967), 10(5), 908-12).
xcex2-L-2xe2x80x2-deoxythymidine (xcex2-L-dT) is known in the art to inhibit herpes simplex virus type 1 (HSV-1) thymidine kinase (TK). Iotti et al., WO 92/08727, teaches that xcex2-L-dT selectively inhibits the phosphorylation of D-thymidine by HSV-1 TK, but not by human TK. Spaldari et al. reported that L-thymidine is phosphorylated by herpes simplex virus type 1 thymidine kinase and inhibits viral growth, J. Med. Chem. (1992), 35(22), 4214-20.
In light of the fact that hepatitis B virus has reached epidemic levels worldwide, and has severe and often tragic effects on the infected patient, there remains a strong need to provide new effective pharmaceutical agents to treat humans infected with the virus that have low toxicity to the host.
Therefore, it is an object of the present invention to provide new methods and compositions for the treatment of human patients or other hosts infected with hepatitis B virus.
A method for the treatment of hepatitis B infection in humans and other host animals is disclosed that includes administering an effective amount of a biologically active 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleoside (referred to alternatively herein as a xcex2-L-d-nucleoside or a xcex2-L-2xe2x80x2-d-nucleoside) or a pharmaceutically acceptable salt or prodrug thereof, administered either alone or in combination, optionally in a pharmaceutically acceptable carrier. The term 2xe2x80x2-deoxy, as used in this specification, refers to a nucleoside that has no substituent in the 2xe2x80x2-position.
The disclosed 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleosides, or pharmaceutically acceptable prodrugs or salts or pharmaceutically acceptable formulations containing these compounds are useful in the prevention and treatment of hepatitis B infections and other related conditions such as anti-HBV antibody positive and HBV-positive conditions, chronic liver inflammation caused by HBV, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue. These compounds or formulations can also be used prophylactically to prevent or retard the progression of clinical illness in individuals who are anti-HBV antibody or HBV-antigen positive or who have been exposed to HBV.
In one embodiment of the present invention, the 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleoside derivative is a compound of the formula: 
wherein R is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate, or a phosphate derivative; and BASE is a purine or pyrimidine base which may optionally be substituted.
In another embodiment, the 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleoside derivative is xcex2-L-2xe2x80x2-deoxyadenosine or a pharmaceutically acceptable salt or prodrug thereof, of the formula: 
wherein R is H, mono, di or tri phosphate, acyl, or alkyl, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug).
In another embodiment, the 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleoside derivative is xcex2-L-2xe2x80x2-deoxycytidine or pharmaceutically acceptable salt or prodrug thereof of the formula: 
wherein R is H, mono, di or tri phosphate, acyl, or alkyl, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug).
In another embodiment, the 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleoside derivative is xcex2-L-2xe2x80x2-deoxyuridine or pharmaceutically acceptable salt or prodrug thereof of the formula: 
wherein R is H, mono, di or tri phosphate, acyl, or alkyl, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug).
In another embodiment, the 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleoside derivative is xcex2-L-2xe2x80x2-deoxyguanosine or pharmaceutically acceptable salt or prodrug thereof of the formula: 
wherein R is H, mono, di or tri phosphate, acyl, or alkyl, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug).
In another embodiment, the 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleoside derivative is xcex2-L-2xe2x80x2-deoxyinosine or pharmaceutically acceptable salt or prodrug thereof of the formula: 
wherein R is H, mono, di or tri phosphate, acyl, or alkyl, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug).
In another embodiment, the 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleoside derivative is xcex2-L-thymidine or a pharmaceutically acceptable salt or prodrug thereof of the formula: 
wherein R is H, mono, di or tri phosphate, acyl, or alkyl, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug).
In another embodiment, the 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleoside is administered in alternation or combination with one or more other 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleosides or one or more other compounds which exhibit activity against hepatitis B virus. In general, during alternation therapy, an effective dosage of each agent is administered serially, whereas in combination therapy, an effective dosage of two or more agents are administered together. The dosages will depend on absorption, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
In another embodiment, the invention includes a method for the treatment of humans infected with HBV that includes administering an HBV treatment amount of a prodrug of the disclosed 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleoside derivatives. A prodrug, as used herein, refers to a compound that is converted into the nucleoside on administration in vivo. Nonlimiting examples include pharmaceutically acceptable salt (alternatively referred to as xe2x80x9cphysiologically acceptable saltsxe2x80x9d), the 5xe2x80x2 and N4 (cytidine) or N6 (adenosine) acylated or alkylated derivatives of the active compound, or the 5xe2x80x2-phospholipid or 5xe2x80x2-ether lipids of the active compound.